Cannabinoid receptor antagonists-inverse agonists useful for treating metabolic disorders, including obesity and diabetes

ABSTRACT

The present invention provides novel pyrazolines that are useful as cannabinoid receptor blockers and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, inflammatory disorders, cardiometabolic disorders, hepatic disorders, and/or cancers.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 61/415,051 filed 18 Nov.2010. The disclosure this application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention provides pyrazoline cannabinoid receptorantagonists/inverse agonists and pharmaceutical compositions thereof andmethods of using the same for treating conditions including obesity,diabetes, hepatic disorders, cardiometabolic disorders, and/or cancers.

BACKGROUND OF THE INVENTION

Obesity is associated with an increase in the overall amount of adiposetissue (i.e., body fat), especially adipose tissue localized in theabdominal area. Obesity has reached epidemic proportions in the UnitedStates. The prevalence of obesity has steadily increased over the yearsamong all racial and ethnic groups. The most recent data from theCenters for Disease Control and Prevention, and the National Center forHealth Statistics report 66% of the adult population overweight (BMI,25.0-29.9), 31% obese (BMI, 30-39.9), and 5% extremely obese (BMI,≧40.0). Among children aged 6 through 19 years, 32% were overweight and17% were obese. This translates to 124 million Americans medicallyoverweight, and 44 million of these deemed obese. Obesity is responsiblefor more than 300,000 deaths annually, and will soon overtake tobaccousage as the primary cause of preventable death in the United States.Obesity is a chronic disease that contributes directly to numerousdangerous co-morbidities, including type 2 diabetes, cardiometabolicdiseases, hepatic disorders, cardiovascular disease, inflammatorydiseases, premature aging, and some forms of cancer. Type 2 diabetes, aserious and life-threatening disorder with growing prevalence in bothadult and childhood populations, is currently the 7^(th) leading causeof death in the United States. Since more than 80% of patients with type2 diabetes are overweight, obesity is the greatest risk factor fordeveloping type 2 diabetes. Increasing clinical evidence indicates thatthe best way to control type 2 diabetes is to reduce weight.

The most popular over-the counter drugs for the treatment of obesity,phenylpropanolamine and ephedrine, and the most popular prescriptiondrugs, fenfluramine, sibutramine and rimonabant, were removed from themarketplace as a result of safety concerns. Drugs currently approved forthe treatment of obesity fall into two categories: (a) CNS appetitesuppressants such as phentermine and Contrave® (naltrexone SR/bupropionSR), and (b) gut lipase inhibitors such as orlistat. CNS appetitesuppressants reduce eating behavior through activation of the ‘satietycenter’ in the brain and/or by inhibition of the ‘hunger center’ in thebrain. Gut lipase inhibitors reduce the absorption of dietary fat fromthe gastrointestinal (GI) tract. Although appetite suppressants and gutlipase inhibitors work through very different mechanisms, they share incommon the same overall goal of reducing body weight secondary toreducing the amount of calories that reach the systemic circulation.Unfortunately, these indirect therapies produce only a modest initialweight loss (approximately 5% compared to placebo) that is usually notmaintained. After one or two years of treatment, most patients return toor exceed their starting weight. In addition, most approved anti-obesitytherapeutics produce undesirable and often dangerous side effects thatcan complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiralingobesity epidemic, positions the ‘treatment of obesity’ as one of thelargest and most urgent unmet medical needs. There is, therefore, a realand continuing need for the development of improved medications thattreat or prevent obesity.

The endocannabinoid system, comprised of the cannabinoid receptors (CB1and CB2) and their endogenous ligands (e.g., anandamide, 2-AG), plays aprominent role in the control of food intake and energy metabolism. CB1receptors are widely expressed in the brain, including cortex,hippocampus, amygdala, pituitary and hypothalamus. CB1 receptors havealso been identified in numerous peripheral organs and tissues,including thyroid gland, adrenal gland, reproductive organs, adiposetissue, liver, muscle, pancreas, kidney, and gastrointestinal tract. CB2receptors are localized almost exclusively in immune and blood cells[Endocrine Reviews 2006, 27, 73].

The plant-derived cannabinoid agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC),the main psychoactive component of marijuana, binds to both CB1 and CB2receptors. Δ⁹-THC is widely reported to increase appetite and foodintake (hyperphagia) in humans and in animals. This hyperphagic effectis largely blocked by pretreatment with selective CB1 receptor blockers(i.e., CB1 blockers) (e.g., rimonabant (SR141716A, Acomplia®)), stronglysupporting the belief that CB1 receptor activation mediates thehyperphagic effect of Δ⁹-THC, [Endocrine Reviews 2006, 27, 73].

In humans, rimonabant produces a clinically meaningful weight loss inobese patients. Obese patients also experience improvements in diabeticand cardiometabolic risk factors associated with obesity, including anincrease in the level of high density lipoprotein cholesterol (HDL), anddecreases in triglycerides, glucose, and hemoglobin A1c (HbA1c, a markerof cumulative exposure to glucose) levels. Rimonabant also producesreductions in abdominal fat deposits, which are a known risk factor fordiabetes and heart disease [Science 2006, 311, 323]. Taken together,these improvements in adiposity and cardiometabolic risk factors producean overall decrease in the prevalence of the metabolic syndrome [Lancet2005, 365, 1389 and NEJM 2005, 353, 2121].

In patients with type 2 diabetes not currently treated with otheranti-diabetic medications, rimonabant was shown to significantly improveblood sugar control and weight, as well as other risk factors such asHDL and triglycerides, when compared to placebo (Lancet 2006, 368(9548),1660-72). After six months of treatment, HbA1c levels were significantlylowered by 0.8% from a baseline value of 7.9 as compared to a reductionof 0.3% in the placebo group. These results are consistent withpreclinical studies that demonstrate improved glycemic and lipid controlin diabetic and dyslipedemic mice, rats, and dogs (PharmacologyBiochemistry & Behavior, 2006, 84, 353; American Journal of Physiology,2003, 284, R345; American Diabetes Association Annual Meeting, 2007;Abstract Number 0372-OR).

The beneficial effects of rimonabant on diabetic and cardiometabolicrisk factors such as high blood pressure, insulin resistance, andelevated triglycerides cannot be explained by diet-related weight lossalone. For example, in patients receiving 20 mg of rimonabant, onlyapproximately 50% of the beneficial effects on triglycerides, fastinginsulin, and insulin resistance can be accounted for by weight losssecondary to reduced food intake. These results suggest a directpharmacological effect of CB1 antagonists on glucose and lipidmetabolism, in addition to indirect effects on metabolism secondary tohypophagia-mediated weight loss [Science 2006, 311, 323 and JAMA 2006,311, 323]. Taken together, these results suggest that CB1 antagonistsmight be effective in the treatment of diabetes, dyslipidemia,cardiovascular disorders (e.g., atherosclerosis, hypertension), andhepatic disorders (e.g., cirrhosis, fatty liver diseases), even inpatients that are not clinically overweight or obese.

The CB1 receptor is one of the most abundant and widely distributed Gprotein-coupled receptors in the mammalian brain. It is now known thatthe appetite-suppressant properties of CB1 antagonists can be mediatedthrough either a direct action with CB1 receptors in brain regionsassociated with hunger and satiety (e.g., hypothalamus, mesolimbicregions), or a direct action with CB1 receptors in peripheral tissues(e.g., adipose tissue, kidney) [J. Clin Invest 2010, 120: 2953; Obesity2011, 19: 1325] However, CB1 receptors are far more broadly distributedin brain (e.g., neocortex, hippocampus, thalamus, cerebellum, andpituitary), and while interacting with targeted CB1 receptors inhypothalamus and mesolimbic regions to suppress appetite, CB1antagonists have equal access to non-targeted CB1 receptors that havelittle if any role in appetite control. Binding to non-targetedreceptors can often lead to unwanted side effects of CNS drugs[Endocrine Reviews 2006, 27: 73]. The CB1 blockers rimonabant andtaranabant produce psychiatric and neurological side effects. Theseinclude depressed mood, anxiety, irritability, insomnia, dizziness,headache, seizures, and suicidality.

These side effects are dose-related and appear pronounced at the mostefficacious weight-reducing doses of rimonabant and taranabant (JAMA2006, 311, 323; Cell Metabolism 2008, 7, 68). The occurrence oftherapeutic efficacy (appetite suppression) and side effects over thesame dose range strongly suggest that both effects are mediated throughconcurrent antagonism of CB1 receptors in both ‘targeted’ and‘non-targeted’ brain regions. Brain-penetrant CB1 blockers do notselectively target CB1 receptors in efficacy brain regions, whileignoring CB1 receptors in side effect brain regions.

The beneficial effects of the CB1 antagonist rimonabant on body weight,adiposity, and diabetic and cardiometabolic risk factors such as highblood pressure, insulin resistance and blood lipids cannot be explainedby weight loss derived from CNS-mediated appetite suppression alone[JAMA 2006, 311, 323]. Approximately 50% of the benefit is likelyderived from an interaction with CB1 receptors in peripheral tissuesknown to play an active role in metabolism. These include adiposetissue, liver, muscle, pancreas, kidney, and gastrointestinal tract.

In view of the above, it is highly desirable to find effective andhighly selective CB1 receptor blockers with limited or no CNS adverseside effects, including mood disorders. Particularly, it is desirable tofind compounds that preferentially target CB1 receptors in peripheraltissues (e.g., adipose tissue, liver, muscle, pancreas, andgastrointestinal tract), while sparing CB1 receptors in brain. In thisway, peripherally-mediated beneficial effects of CB1 blockers can bemaintained, whereas CNS side effects will be reduced or eliminated. Thisshould provide a novel opportunity to develop safer alternatives tohighly brain penetrant CB1 blockers for the prevention or treatment ofobesity, diabetes, dyslipidemia, cardiovascular disorders, hepaticdisorders, and/or certain cancers.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novelpyrazolines or pharmaceutically acceptable salts thereof that are CB1receptor antagonists/inverse agonists.

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods fortreating obesity, diabetes (e.g., insulin resistance, inadequate glucosetolerance, Type I diabetes, and Type II diabetes), dyslipidemias (e.g.,elevated triglycerides and LDL, and low HDL), cardiovascular disorders(e.g., atherosclerosis and hypertension), inflammatory disorders (e.g.,osteoarthritis, rheumatoid arthritis, inflammatory bowel diseases, andobesity-associated inflammation), hepatic disorders (e.g., nonalcoholicand alcoholic steatohepatitis, cirrhosis and fatty liver disease),and/or cancer (e.g., colon, breast, thyroid, and alveolarrhabdomyosarcoma cancer), comprising: administering to a mammal in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt form thereof.

In another aspect, the present invention provides processes forpreparing novel compounds.

In another aspect, the present invention provides novel compounds orpharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment ofobesity, diabetes, dyslipidemia, cardiovascular disorders, and/orhepatic disorders, and/or certain cancers.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed compounds or pharmaceutically acceptable saltforms thereof are expected to be effective CB1 receptor blockers.

DETAILED DESCRIPTION OF THE INVENTION

All references cited herein are hereby incorporated in their entiretyherein by reference.

A CB1 blocker is a neutral CB1 receptor antagonist and/or a CB1 receptorinverse agonist.

The present invention is based on the finding that a CB1 receptorblocker has beneficial effects on cardiometabolic disorders includingobesity, diabetes, dyslipidemias, and liver diseases that cannot beexplained by weight loss derived from CNS-mediated appetite suppressionalone, and that this effect is mediated, at least in part, throughinteraction at peripheral CB1 receptors. To this end, the presentinvention provides compounds that are designed to preferentially targetCB1 receptors in peripheral tissues (e.g., adipose tissue, liver,muscle, pancreas, kidney, and gastrointestinal tract), while sparing CB1receptors in brain. With these types of compounds, peripherally-mediatedbeneficial effects of CB1 blockers should be maintained, whereas CNSside effects should be reduced or eliminated.

The compounds of the present invention have been designed to havereduced CNS exposure by virtue of their inability or limited ability topenetrate the blood-brain barrier (BBB), or by their participation inactive transport systems, thus reducing centrally mediated side-effects,a potential problem with many anti-obesity agents. It is expected thatthe peripherally restricted compounds of the present invention will haveno or very limited CNS effects, including mood disorders, seizures, andsuicidality. Thus, their peripherally mediated CB1 antaonisticproperties should provide therapeutic agents with greater safety.

Moreover, if the maximum dosage of a drug used in the treatment ofobesity, diabetes, dyslipidemia, cardiovascular disorders, inflammatorydisorders, hepatic disorders, and/or cancers is limited as a result ofCNS side effects (e.g., seizures, depression, anxiety, suicidality,movement disorders, and hyperactivity), incorporation of a peripherallyrestricting group in such a drug would lower the brain concentration ofthe drug relative to the concentration in the systemic circulation,thereby affording the opportunity to increase the dosage employed totreat the peripheral disorder (e.g., obesity, diabetes, dyslipidemia,cardiovascular disorders, inflammatory disorders, hepatic disorders,and/or cancers). The increased dosage may provide greater therapeuticefficacy, as well as a more rapid onset of therapeutic action.

[1] In an embodiment, the present invention provides novel compound ofFormula I or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₆ alkyl,halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CN,OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂,NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂R, NR^(a)CO(CH₂)_(n)CO₂R,NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂,O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole,NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a)₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, CONHOH, C(NH)NR^(a) ₂,(CH₂)_(n)C(NH)NR^(a) ₂, O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NR^(a) ₂,O(CH₂)_(n)C(NOH)NR^(a) ₂, CH₂O(CH₂)_(n)CONR^(a) ₂,NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂,NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃;

Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R,OC(O)—C₁₋₆ alkyl, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, O(CH₂)_(n)C(NOH)NR^(a) ₂,OCH₂CH═CHCONR^(a) ₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Z′ is selected from H, CO₂R, and CONR^(a) ₂;

Q is selected from: (CH₂)_(n)CHA(CH₂)_(m)C(O)NR₂,(CH₂)_(m)CAA″(CH₂)_(m)C(O)NR₂, (CH₂)_(n)CHA(CH₂)_(m)CO₂R,(CH₂)_(m)CAA″(CH₂)_(m)CO₂R, (CH₂)_(m)CHA(CH₂)_(m)SO₂NR₂,(CH₂)_(m)CHA(CH₂)_(m)SO₃R, (CH₂)_(m)CHA(CH₂)_(m)C(NH)NH₂,(CH₂)_(m)CHA(CH₂)_(m)C(NOH)NH₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,C₃-C₆-cyclic amino-(CH₂)_(m)CO₂R, C₃-C₆-cyclic amino-(CH₂)_(m)CONR^(a)₂, C₃-C₆-cycloalkylene-(CH₂)_(m)CO₂R,C₃-C₆-cycloalkylene-(CH₂)_(m)CONR^(a) ₂, (CH₂)_(n)CH═CHCO₂R,(CH₂)_(n)CH═CHCONR^(a) ₂, (CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a)₂, (CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)-aryl-(CH₂)_(m)CO₂R, (CH₂)_(m)-aryl-(CH₂)_(m)CONR^(a) ₂,heteroaryl-(CH₂)_(m)CO₂R, heteroaryl-(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)PO₃R₂, (CH₂)_(m)CAA″(CH₂)_(m)PO₃R₂,(CH₂)_(m)CHA(CH₂)_(m)PO(OR)NR^(a), (CH₂)_(m)CAA″(CH₂)_(m)PO(OR)NR^(a),(CH₂)_(m)CAA″(CH₂)_(m)PONR^(a) ₂, and (CH₂)_(m)CHA(CH₂)_(m)PONR^(a) ₂;

A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl, OH, CH₂OH,CH(CH₃)OH, C(CH₃)₂OH, (CH₂)_(n)CO₂R^(b), (CH₂)_(n)C(O)NR^(b) ₂, and(CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groupsselected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, CONR^(c)₂, CO₂R, NR₂, OR, NHSO₂CH₃, NHCONH₂, and SONHR;

A″ is C₁₋₆ alkyl;

alternatively, the CAA″ group forms a C₃₋₆ spiro cycloalkyl ring or 4-6membered spiro cycloalkylamine ring;

M is C═O or SO₂;

R is independently selected from H, (CH₂)_(m)(CHR^(b))_(n)(CH₂)_(m)OH,CH(CH₂OH)₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(a) is independently selected from H, (CH₂)_(m)(CHR)_(n)(CH₂)_(m)OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(b) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, 3, and 4; and,

n is selected from 1, 2, 3, and 4;

provided that either at least one of (a)-(c) is satisfied:

-   -   (a) Q is selected from (CH₂)_(n)CH═CHCO₂R,        (CH₂)_(n)CH═CHCONR^(a) ₂,        (CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,        (CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,        (CH₂)_(m)CHA(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,        (CH₂)_(m)CAA″(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,        (CH₂)_(m)-aryl-(CH₂)_(m)CO₂R, (CH₂)_(m)-aryl-(CH₂)_(m)CONR^(a)        ₂, heteroaryl-(CH₂)_(m)CO₂R, heteroaryl-(CH₂)_(m)CONR^(a) ₂,        (CH₂)_(m)CHA(CH₂)_(m)PO₃R₂, (CH₂)_(m)CAA″(CH₂)_(m)PO₃R₂,        (CH₂)_(m)CHA(CH₂)_(m)PO(OR)NR^(a),        (CH₂)_(m)CAA″(CH₂)_(m)PO(OR)NR^(a),        (CH₂)_(m)CAA″(CH₂)_(m)PONR^(a) ₂, and        (CH₂)_(m)CHA(CH₂)_(m)PONR^(a) ₂;    -   (b) the CAA″ group forms a C₃₋₆ spiro cycloalkyl ring or 4-6        membered spiro cycloalkylamine ring; and,    -   (c) A is (CH₂)_(m)-phenyl, wherein the phenyl is substituted        with 1 group selected from CONR^(c) ₂, CO₂R, NR₂, OR, NHSO₂CH₃,        NHCONH₂, and SONHR and 0-2 groups selected from H, C₁₋₄ alkyl,        halogen, CF₃, O—C₁₋₄ alkyl, NO₂, CONR^(c) ₂, CO₂R, NR₂, OR,        NHSO₂CH₃, NHCONH₂, and SONHR.

In another embodiment, the present invention provides novel compoundswherein: M is SO₂.

[2] In another embodiment, the present invention provides novelcompounds of formula Ia or a stereoisomer or pharmaceutically acceptablesalt thereof,

[3] In another embodiment, the present invention provides novelcompounds of formula Ib or a stereoisomer or pharmaceutically acceptablesalt thereof,

[4] In another embodiment, the present invention provides novelcompounds of formula Ic or a stereoisomer or pharmaceutically acceptablesalt thereof,

[5] In another embodiment, the present invention provides novelcompounds of formula Ia or a stereoisomer or pharmaceutically acceptablesalt thereof,

wherein:

X, Y, X′, Y′, X″, and Y″ are individually selected from the following:H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R,NR^(a)(CH₂CH₂O)_(p)R, and NR₂;

Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, andpropionyloxy;

Q is selected from: (CH₂)_(n)CHA(CH₂)_(m)C(O)NR₂,(CH₂)_(m)CAA″(CH₂)_(m)C(O)NR₂, (CH₂)_(n)CHA(CH₂)_(m)CO₂R,(CH₂)_(m)CAA″(CH₂)_(m)CO₂R, (CH₂)_(m)CHA(CH₂)_(m)SO₂NR₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONHCHA(CH₂)_(m)CO₂R,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,C₃-C₆-cyclic amino-(CH₂)_(m)CO₂R, C₃-C₆-cyclic amino-(CH₂)_(m)CONR^(a)₂, C₃-C₆-cycloalkylene-(CH₂)_(m)CO₂R,C₃-C₆-cycloalkylene-(CH₂)_(m)CONR^(a) ₂, (CH₂)_(n)CH═CHCO₂R,(CH₂)_(n)CH═CHCONR^(a) ₂, (CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a)₂, (CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)-aryl-(CH₂)_(m)CO₂R, (CH₂)_(m)-aryl-(CH₂)_(m)CONR^(a) ₂,heteroaryl-(CH₂)_(m)CO₂R, heteroaryl-(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)PO₃R₂, (CH₂)_(m)CAA″(CH₂)_(m)PO₃R₂,(CH₂)_(m)CHA(CH₂)_(m)PO(OR)NR^(a), (CH₂)_(m)CAA″(CH₂)_(m)PO(OR)NR^(a),(CH₂)_(m)CAA″(CH₂)_(m)PONR^(a) ₂, and (CH₂)_(m)CHA(CH₂)_(m)PONR^(a) ₂;

A is selected from H, C₁₋₄ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl, OH, CH₂OH,CH(CH₃)OH, C(CH₃)₂OH, (CH₂)_(n)CO₂R^(b), (CH₂)_(n)C(O)NR^(b) ₂, and(CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groupsselected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, CONR^(c)₂, CO₂R, NR₂, OR, NHSO₂CH₃, NHCONH₂, and SONHR;

alternatively, the CAA″ group forms a C₃₋₆ spiro cycloalkyl ring or 4-6membered spiro cycloalkylamine ring;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

R^(b) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, and 8;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

[5] In another embodiment, the present invention provides novelcompounds of formula Ia or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein:

Q is selected from: (CH₂)_(n)CHA(CH₂)_(m)C(O)NR₂,(CH₂)_(m)CAA″(CH₂)_(m)C(O)NR₂, (CH₂)_(m)CHA(CH₂)_(m)SO₂NR₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONHCHA(CH₂)_(m)CONR^(a) ₂,C₃-C₆-cyclic amino-(CH₂)_(m)CO₂R, C₃-C₆-cyclic amino-(CH₂)_(m)CONR^(a)₂, C₃-C₆-cycloalkylene-(CH₂)_(m)CONR^(a) ₂, (CH₂)_(n)CH═CHCONR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCHA(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CHA(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)CAA″(CH₂)_(m)CONHCAA″(CH₂)_(m)SO₂NR^(a) ₂,(CH₂)_(m)-aryl-(CH₂)_(m)CONR^(a) ₂, heteroaryl-(CH₂)_(m)CO₂R,heteroaryl-(CH₂)_(m)CONR^(a) ₂, (CH₂)_(m)CHA(CH₂)_(m)PO₃R₂,(CH₂)_(m)CAA″(CH₂)_(m)PO₃R₂, (CH₂)_(m)CHA(CH₂)_(m)PO(OR)NR^(a),(CH₂)_(m)CAA″(CH₂)_(m)PO(OR)NR^(a), (CH₂)_(m)CAA″(CH₂)_(m)PONR^(a) ₂,and (CH₂)_(m)CHA(CH₂)_(m)PONR^(a) ₂;

M is SO₂;

alternatively, the CAA″ group forms a C₃₋₆ spiro cycloalkyl ring or 4-6membered spiro cycloalkylamine ring;

R is independently selected from H and C₁₋₄ alkyl;

R^(b) is independently selected from H and C₁₋₄ alkyl;

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1 and 2.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method ofmodulating the activity of CB1 receptors (e.g., periperhal CB1receptors) in a patient, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method oftreating a disease characterized by an inappropriate activation ofperipheral CB1 receptors, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a disease mediated by the CB₁ receptor in a patient,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt form thereof. In an example, thedisease is mediated by peripheral CB₁ receptors. In another example, theCB₁ receptors that are blocked are peripheral CB₁ receptors.

In another embodiment, the present invention provides a novel method fortreating a disease, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof, whereinthe disease is selected from obesity, diabetes, dyslipidemias,cardiovascular disorders, inflammatory disorders, hepatic disorders,cancers, and a combination thereof.

In another embodiment, the diabetes disorder is selected from Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulinresistance.

In another embodiment, the dyslipidemia disorder is selected fromundesirable blood lipid levels, including low levels of high-densitylipoprotein, high levels of low-density lipoprotein, high levels oftriglycerides, and a combination thereof.

In another embodiment, the cardiovascular disorder is selected fromatherosclerosis, hypertension, stroke and heart attack.

In another embodiment, the inflammatory disorder is selected fromosteoarthritis, rheumatoid arthritis, inflammatory bowel diseases, andobesity-associated inflammation.

In another embodiment, the hepatic disorder is selected from liverinflammation, liver fibrosis, non-alcoholic steatohepatitis, fattyliver, enlarged liver, alcoholic liver diseases, jaundice, cirrhosis,and hepatitis.

In another embodiment, the cancer is selected from colon, breast,thyroid, and alveolar rhabdomyosarcoma.

In another embodiment, the present invention provides a novel method fortreating a co-morbidity of obesity, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the co-morbidity is selected from diabetes,dyslipidemias, Metabolic Syndrome, dementia, cardiovascular disease, andhepatic disease.

In another embodiment, the co-morbidity is selected from hypertension;gallbladder disease; gastrointestinal disorders; menstrualirregularities; degenerative arthritis; venous statis ulcers; pulmonaryhypoventilation syndrome; sleep apnea; snoring; coronary artery disease;arterial sclerotic disease; pseudotumor cerebri; accident proneness;increased risks with surgeries; osteoarthritis; high cholesterol; and,increased incidence of malignancies of the ovaries, cervix, uterus,breasts, prostrate, and gallbladder.

In another embodiment, the present invention also provides a method ofpreventing or reversing the deposition of adipose tissue in a mammal bythe administration of a compound of the present invention. By preventingor reversing the deposition of adipose tissue, compound of the presentinvention are expected to reduce the incidence or severity of obesity,thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use of thepresent invention for the manufacture of a medicament for the treatmentof an indication recited herein (e.g., obesity, diabetes, dyslipidemias,cardiovascular disorders, inflammatory disorders, hepatic disorders,cancers, and a combination thereof).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also to beunderstood that each individual element of the embodiments is intendedto be taken individually as its own independent embodiment. Furthermore,any element of an embodiment is meant to be combined with any and allother elements from any embodiment to describe an additional embodiment.

DEFINITIONS

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

Examples of the molecular weight of the compounds of the presentinvention include (a) less than about 500, 550, 600, 650, 700, 750, 800,850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams permole; (c) less than about 850 grams per mole; and, (d) less than about750 grams per mole.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Cyclic amine” is a hydrocarbon ring wherein one carbon atom of the ringhas been replaced by a nitrogen atom. The cyclic amine can beunsaturated, partially saturated, or fully saturated. The cyclic aminecan also be bicyclic, tricyclic, and polycyclic. Examples of cyclicamine include pyrrolidine and piperidine.

Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species,such as chloride, bromide, hydroxide, acetate, and sulfate.

The group “C₆H₄” represents a phenylene.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Mammal” and “patient” cover warm blooded mammals that are typicallyunder medical care (e.g., humans and domesticated animals). Examplesinclude feline, canine, equine, bovine, and human, as well as justhuman.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting it development; and/or (c)relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare useful. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat obesity, diabetes, dyslipidemias, cardiovasculardisorders, inflammatory disorders, hepatic disorders, cancers, and acombination or comorbitity thereof, or another indication listed herein.“Therapeutically effective amount” also includes an amount of thecombination of compounds claimed that is effective to treat the desiredindication. The combination of compounds can be a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of thecompounds when administered in combination is greater than the additiveeffect of the compounds when administered alone as a single agent. Ingeneral, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased effect, or some other beneficial effect ofthe combination compared with the individual components.

Obesity is defined as having a body mass index (BMI) of 30 or above. Theindex is a measure of an individual's body weight relative to height.BMI is calculated by dividing body weight (in kilograms) by height (inmeters) squared. Normal and healthy body weight is defined as having aBMI between 20 and 24.9. Overweight is defined as having a BMI≧25.Obesity has reached epidemic proportions in the U.S., with 44 millionobese Americans, and an additional eighty million deemed medicallyoverweight.

Obesity is a disease characterized as a condition resulting from theexcess accumulation of adipose tissue, especially adipose tissuelocalized in the abdominal area. It is desirable to treat overweight orobese patients by reducing their amount of adipose tissue, and therebyreducing their overall body weight to within the normal range for theirsex and height. In this way, their risk for co-morbidities such asdiabetes, dyllipidemias, cardiovascular disorders, inflammatorydisorders, hepatic disorders, and cancers will be reduced. It is alsodesirable to prevent normal weight individuals from accumulatingadditional, excess adipose tissue, effectively maintaining their bodyweights at a BMI<25, and preventing the development of co-morbidities.It is also desirable to control obesity, effectively preventingoverweight and obese individuals from accumulating additional, excessadipose tissue, reducing the risk of further exacerbating theirco-morbidities.

Type 2 Diabetes or Diabetes mellitus type 2 or (formerly callednon-insulin-dependent diabetes mellitus (NIDDM), or adult-onsetdiabetes) is a metabolic disorder that is primarily characterized byinsulin resistance, relative insulin deficiency, glucose intolerance,and/or hyperglycemia. The World Health Organization definition ofdiabetes is for a single raised glucose reading with symptoms otherwiseraised values on two occasions, of either fasting plasma glucose ≧7.0mmol/l (126 mg/dl) or with a Glucose tolerance test: two hours after theoral dose a plasma glucose ≧11.1 mmol/l (200 mg/dl). Type 2 Diabetes israpidly increasing in the developed world and there is some evidencethat this pattern will be followed in much of the rest of the world incoming years. CDC has characterized the increase as an epidemic(Diabetes, Atlanta: Centres for Disease Control, Atlanta, Report no.2007-05-24). In addition, whereas this disease used to be seen primarilyin adults over age 40 (in contrast to Diabetes mellitus type 1), it isnow increasingly seen in children and adolescents, an increase thoughtto be linked to rising rates of obesity in this age group.

Insulin resistance means that body cells do not respond appropriatelywhen insulin is present. Unlike insulin-dependent diabetes mellitus(Type 1), the insulin resistance is generally “post-receptor”, meaningit is a problem with the cells that respond to insulin rather than aproblem with insulin production. Type 2 diabetes is presently of unknownetiology (i.e., origin). About 90-95% of all North American cases ofdiabetes are type 2, and about 20% of the population over the age of 65has diabetes mellitus Type 2 (Nature, 2001, 414, 6865). Diabetes affectsover 150 million people worldwide and this number is expected to doubleby 2025. About 55 percent of type 2 diabetics are obese-chronic obesityleads to increased insulin resistance that can develop into diabetes(Morbidity and Mortality Weekly Report 2008, 53, 1066). Type 2 diabetesis often associated with obesity, hypertension, elevated cholesterol(combined hyperlipidemia), and with the condition often termed Metabolicsyndrome (it is also known as Syndrome X, Reavan's syndrome, or CHAOS).There are several drugs available for Type 2 diabetics, includingmetformin, thiazolidinediones, which increase tissue insulinsensitivity, α-glucosidase inhibitors which interfere with absorption ofsome glucose containing nutrients, and peptide analogs that must beinjected.

Dyslipidemia is the presence of abnormal levels of lipids and/orlipoproteins in the blood. Lipids (fatty molecules) are transported in aprotein capsule, and the density of the lipids and type of proteindetermines the fate of the particle and its influence on metabolism.Lipid and lipoprotein abnormalities are extremely common in the generalpopulation, and are regarded as a highly modifiable risk factor forcardiovascular disease due to the influence of cholesterol, one of themost clinically relevant lipid substances, on atherosclerosis. Inaddition, some forms may predispose to acute pancreatitis.

In western societies, most dyslipidemias are hyperlipidemias; that is,an elevation of lipids in the blood, often due to diet and lifestyle.The prolonged elevation of insulin levels can also lead to dyslipidemia.The most prevalent hyperlipidemias include: hypercholesterolemia,characterized by elevated cholesterol (usually LDL),hypertriglyceridemia, characterized by elevated triglycerides (TGs);hyperlipoproteinemia, characterized by elevated lipoproteins;hyperchylomicronemia, characterized by elevated chylomicrons; andcombined hyperlipidemia, characterized by elevated LDL andtriglycerides. Abnormal decreases in the levels of lipids and/orlipoproteins in the blood also can occur. These includehypocholesterolemia, characterized by lowered cholesterol (usually highdensity lipoprotein, or HDL); and abetalipoproteinemia, characterized bylowered beta lipoproteins.

Dyslipidemia contributes to the development of atherosclerosis. Causesmay be primary (genetic) or secondary. Diagnosis is by measuring plasmalevels of total cholesterol, TGs, and individual lipoproteins. Treatmentis dietary changes, exercise, and lipid-lowering drugs. A linearrelation probably exists between lipid levels and cardiovascular risk,so many people with “normal” cholesterol levels benefit from achievingstill lower levels. Normal and abnormal lipid levels have been definedin the Third Report of the Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults. National Institutes ofHealth, National Heart, Lung, and Blood Institute, 2001.

The treatment of choice for dyslipidemias is lifestyle change, includingdiet and exercise. Drugs are the next step when lifestyle changes arenot effective. Lipid lowering drugs include statins, nicotinic acid,bile acid sequestrants, fibrates, cholesterol absorption inhibitors, andcombination treatments (e.g., niacin and a statin). These agents are notwithout adverse effects, including flushing and impaired glucosetolerance (nicotinic acid), bloating, nausea, cramping, and constipation(bile acid sequestrants). Bile acid sequestrants may also increase TGs,so their use is contraindicated in patients with hypertriglyceridemia.Fibrates potentiate muscle toxicity when used with statins, and mayincrease LDL in patients with high TGs.

There are many kinds of hepatic (i.e., liver) diseases. Viruses causesome of them, like hepatitis A, hepatitis B and hepatitis C. Others canbe the result of drugs, poisons or drinking too much alcohol. If theliver forms scar tissue because of an illness, it's called cirrhosis.Jaundice, or yellowing of the skin, can be one sign of hepatic disease.Cancer can affect the liver. Hepatic diseases such as hemochromatosiscan be inherited. Additional liver diseases include nonalcoholsteatohepatitis (NASH), alcoholic liver disease, cholangiocarcinoma,hepatic encephalopathy, hepatic failure, liver abscess, liver tumors,liver coagulopathy, glycogen storage diseases, portal hypertension,primary biliary cirrhosis, and primary sclerosing cholangitis.

There are few good treatment options for liver diseases. Options includelifestyle change (including diet and exercise), liver transplantation,and insertion of a transjugular intrahepatic portosystemic shunt that isplaced in veins in the middle of the liver to improve blood flow to andfrom the organ. There are few effective drug treatment options forhepatic diseases. Interferon is an FDA-approved drug for the treatmentof viral hepatitis. The chimeric protein Hyper-IL-6 dramaticallyenhances hepatocyte proliferation and is currently being evaluated as apharmacological treatment for liver injury.

Drugs enter the CNS from the systemic circulation by crossing theblood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’that protects the brain by preventing the entry of many potentiallyharmful substances into the CNS from the systemic circulation. Much isknown about the BBB, and of the physical-chemical properties requiredfor compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readilyeliminated through transport mechanisms (J. Clin. Invest. 1996, 97,2517) are known in the literature and have low CNS activity due to theirinability to develop brain levels necessary for pharmacological action.The BBB has at least one mechanism to remove drugs prior to theiraccumulation in the CNS. P-Glycoproteins (P-gp) localized in plasmamembrane of the BBB can influence the brain penetration andpharmacological activity of many drugs through translocation acrossmembranes. The lack of accumulation into the brain by some drugs can beexplained by their active removal from the brain by P-gp residing in theBBB. For example, the typical opioid drug loperamide, clinically used asan antidiarrheal, is actively removed from the brain by P-gp, thusexplaining its lack of opiate-like CNS effects. Another example isdomperidone, a dopamine receptor blocker that participates in the P-gptransport (J. Clin. Invest. 1996, 97, 2517). Whereas dopamine receptorblockers that cross the BBB can be used to treat schizophrenia, thereadily-eliminated domperidone can be used to prevent emesis, withoutthe likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structuralcharacteristics that retard or prevent BBB penetration or contribute toparticipation in active elimination processes have been identified invarious classes of therapeutics. These include antihistamines (DrugMetab. Dispos. 2003, 31, 312), beta-adrenergic receptor antagonists(Eur. J. Clin. Pharmacol. 1985, 28, Suppl: 21; Br. J. Clin. Pharmacol.,1981, 11, 549), non-nucleoside reverse transcriptase inhibitors (NNRTIs,J. Pharm. Sci., 1999, 88, 950), and opioid antagonists. This lattergroup has been tested in relation to their activity in thegastrointestinal tract. These peripherally selective opioid antagonistsare described in various US patents as being useful in the treatment ofnon-CNS pathologies in mammals, in particular those of thegastrointestinal tract [see U.S. Pat. No. 5,260,542; U.S. Pat. No.5,434,171; U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238].

Other types of non-brain penetrant compounds can be prepared through thecreation of a charge within the molecule. Thus, the addition of a methylgroup to the tertiary amine functionality of the drugs scopolamine oratropine, unlike the parent molecules, prevents their passage across theBBB through the presence of a positive charge. However, the newmolecules (methyl-scopolamine and methyl-atropine) retain their fullanticholinergic pharmacological properties. As such, these drugs canalso be used to treat peripheral diseases, without the concern ofadverse CNS effects. The quaternary ammonium compound methylnaltrexoneis also used for the prevention and/or treatment of opioid-inducedgastrointestinal side effects associated with opioid administration (J.Pharmacol. Exp. Ther. 2002, 300, 118).

The discovery that the anti-obesity activity of cannabinoid receptorblockers is in part mediated by a non-CNS mechanism makes it beneficialfor the compounds of the present invention to be peripherally restricted(i.e., have an inability or limited ability to cross the BBB, or bereadily eliminated from the brain through active transport systems). Itmay be desirable for the compounds of the present invention to beperipherally restricted, which in turn will result in no or very limitedCNS effects. Compounds that provide peripherally mediated efficacy intreating obesity, diabetes, dyslipidemias, cardiovascular disorders,inflammatory disorders, hepatic disorders, cancers, a comorbititythereof, or a combination or should result in therapeutic agents withgreater safety. It can be desirable that the compounds of the presentinvention, when administered in a therapeutically effective amount, haveno or very limited CNS effects. It can also be desirable that the lackof CNS effects is a result of the compounds of the present inventionhaving minimal brain concentrations when administered in therapeuticallyeffective amounts. In this context, minimal brain concentrations meanslevels that are too low to be therapeutically effective for thetreatment of a CNS indication or too low to cause significant ormeasurable deleterious or undesired side effects, or both.

SLV319 (Compound I when X and X″ are 4-Cl; X′, Y, Y′, Y″, Z, and Z′ areH; Q is CH₃; and M is SO₂) is a drug that crosses the BBB and isindicated for the treatment of obesity. It is believed that SLV319 worksto treat obesity via a CNS mechanism. Compounds like SLV319 and compoundAA have been described in various publications including J. Med. Chem.2004, 47(3), 627 and U.S. Pat. No. 6,476,060.

In compound AA, one of X, Y, X′, Y′, X″, Y, Z, Z′, or Q is a groupcapable of reducing or limiting the CNS activity of compound AA. Thisreduced or limited CNS activity occurs via at least one of X, Y, X′, Y′,X″, Y, Z, Z′, and Q being a group that either limits compound AA'sability to cross the BBB relative to that of SLV319 or enables it to beactively removed from the brain at a rate greater than that of SLV319.Examples of the amount of compound AA present in the brain can include(a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, to 100% lower than SLV319, (b) from 90, 91, 92, 93, 94, 95, 96,97, 98, 99, to 100% lower than SLV319, and (c) from 98, 99, to 100%lower than SLV319, when administered at the same dosage.

The compounds of the present invention have been shown to be activecannabinoid receptor blockers (e.g., have activity at ≦10 μM). Thecompounds of the present invention are typically CB1 cannabinoidreceptor blockers. However, CB1 blockers frequently are also CB2blockers (i.e., CB2 antagonists or inverse agonists). Thus the presentinvention also includes CB2 blockers and compounds that are both CB1 andCB2 blockers.

An inverse agonist is a compound that not only blocks the action of theendogenous agonist at the receptor, but also exhibits its own activitywhich is usually the opposite of that shown by the agonist. Inverseagonists are also effective against certain types of receptors (e.g.certain histamine receptors/GABA receptors) that have intrinsic activitywithout the interaction of a ligand upon them (also referred to as‘constitutive activity’).

Most methods of treating obesity are dependent on a significantreduction in energy intake, either by a decrease in food intake (e.g.,sibutramine) or by inhibition of fat absorption (e.g., orlistat). In thepresent invention, adipose tissue may be reduced in the absence of asignificant reduction in food intake. The weight loss, as a result ofthe present invention, comes from the treatment with a compound of thepresent invention, largely independent of, though not totallydissociated from, appetite and food intake. It can be desirable thatadipose tissue loss occurs while food intake is maintained, increased or(a) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel), (b) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15%below its pre-administration level, (c) about 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10% below its pre-administration level, or (d) about 1, 2, 3, 4, or5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of lean muscle mass. This is particularly evident incancer patients who show a generalized wasting of body tissues,including adipose tissue and lean muscle mass. In the present invention,however, it can be desirable for body fat to be significantly reduced inthe absence of a significant reduction in lean body mass. Adipose tissueloss comes from treatment with a compound of the present invention,independent of a significant change in lean body mass. Thus, adiposetissue loss can occur while lean body mass is maintained, increased, or(a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% belowthe normal range of the subject prior to being treated in accordancewith the present invention (i.e., its pre-administration level), (b) isno more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15%below pre-administration levels, (c) is no more than about 1, 2, 3, 4,5, 6, 7, 8, 9, or 10% below pre-administration levels, or (d) is no morethan about 1, 2, 3, 4, or 5% below pre-administration levels.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of water mass. This is particularly evident with dietregimens that promote dehydration. In the present invention, it can bedesirable for body fat to be significantly reduced in the absence of asignificant reduction in water mass. In other words, adipose tissue losscomes from treatment with a compound of the present invention,independent of a significant change in water mass. It can be desirablethat adipose tissue loss occurs while water mass is maintained,increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel), (b) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, or 15% below pre-administration levels, (c) is no more thanabout 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels,or (d) is no more than about 1, 2, 3, 4, or 5% below pre-administrationlevels.

Phentermine and orlistat are currently marketed for use in the treatmentof obesity, albeit weight loss is achieved through entirely differentmechanism of action. Phentermine inhibits appetite via a direct brainaction, and orlistat inhibits gut lipase enzymes that are responsiblefor breaking down ingested fat.

Cannabinoid receptor blockers can promote weight loss through inhibitionof peripheral cannabinoid receptors, a mechanism entirely different fromdirect brain appetite suppressants, gut lipase inhibitors, and otheragents with similar indications (e.g., serotonin agonists, leptin, fattyacid synthase inhibitors, and monoamine oxidase (MAO) inhibitors).Co-administration of a cannabinoid receptor blocker together with one ormore other agents that are useful for treating the indications describedabove (e.g., obesity, diabetes, dyslipidemias, cardiovascular disorders,inflammatory disorders, hepatic disorders, cancers, and a combinationthereof) is expected to be beneficial, by producing, for example, eitheradditive or synergistic effects. Examples of additional agents includean appetite suppressant, a lipase inhibitor, and a MAO inhibitor (e.g.,MAO-B and a combination of MAO-A/B). Therefore, the present inventionprovides a method of treating obesity, diabetes, dyslipidemias,cardiovascular disorders, inflammatory disorders, hepatic disorders,and/or cancers, and a combination thereof, comprising administering atherapeutically effective amount of a compound of the present inventionand a second component effective for treating the desired indication.

Examples of second components include anti-obesity agents, whichinclude, but are not limited to: 1) growth hormone secretagogues; 2)growth hormone secretagogue receptor agonists/antagonists; 3)melanocortin agonists; 4) Mc4r (melanocortin 4 receptor) agonists; 5).beta.-3 agonists; 7) 5HT2C (serotonin receptor 2C) agonists; 8) orexinantagonists; 9) melanin concentrating hormone antagonists; 10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists; 11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A)agonists; 16) corticotropin-releasing hormone agonists; 17) NPY 5antagonists; 18) NPY 1 antagonists; 19) histamine receptor-3 (H3)modulators; 20) histamine receptor-3 (H3) blockers; 21) β-hydroxysteroid dehydrogenase-1 inhibitors (.beta.-HSD-1); 22) PDE(phosphodiesterase) inhibitors; 23) phosphodiesterase-3B (PDE3B)inhibitors; 24) NE (norepinephrine) transport inhibitors; 25)non-selective serotonin/norepinephrine transport inhibitors, such assibutramine, phentermine, or fenfluramine; 26) ghrelin antagonists; 28)leptin derivatives; 29) BRS3 (bombesin receptor subtype 3) agonists; 30)CNTF (Ciliary neurotrophic factors); 31) CNTF derivatives, such asaxokine (Regeneron); 32) monoamine reuptake inhibitors; 33) UCP-1(uncoupling protein-1), 2, or 3 activators; 34) thyroid hormone .beta.agonists; 35) FAS (fatty acid synthase) inhibitors; 37) DGAT2(diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoAcarboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40)acyl-estrogens; 41) lipase inhibitors, such as orlistat (Xenical®); 42)fatty acid transporter inhibitors; 43) dicarboxylate transporterinhibitors; 44) glucose transporter inhibitors; 45) phosphatetransporter inhibitors; 46) serotonin reuptake inhibitors; 47) Metformin(Glucophage®); 48) Topiramate (Topimax®); 49) opiate antagonists such asnaltrexone, 50) the non-selective transport inhibitor bupropion, and/or51) MAO inhibitors.

Examples of MAO inhibitors include Moclobemide; Brofaromine; BW A616U;Ro 41-1049; RS-2232; SR 95191; Harmaline; Harman; Amiflamine; BW1370U87; FLA 688; FLA 788; Bifemelane; Clorgyline; LY 51641; MDL 72,394;544-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one;5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazoles; Lazabemide; Ro16-6491; Almoxatone; XB308; RS-1636; RS-1653; NW-1015; SL 340026;L-selegiline; Rasagiline; Pargyline; AGN 1135; MDL 72,974; MDL 72,145;MDL 72,638; LY 54761; MD 780236; MD 240931; Bifemelane; Toloxatone;Cimoxatone; Iproniazid; Phenelzine; Nialamide; Phenylhydrazine;1-Phenylcyclopropylamine; Isocarboxazid; and, Tranylcypromine.Additional examples of MAO inhibitors can be found in USPA 2007/0004683;U.S. application Ser. No. 11/445,044; USPA 2007/0015734; and U.S.application Ser. No. 11/424,274.

Examples of diabetes disorders include treating Type 1 diabetes, Type 2diabetes, inadequate glucose tolerance, and insulin resistance.

Examples of second components useful for treating diabetes include (a)insulin sensitizers including (i) PPAR-γ agonists such as the glitazones(e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone),and compounds disclosed in WO97/27857, 97/28115, 97/28137, and 97/27847;and (ii) biguanides such as metformin and phenformin; (b) insulin orinsulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide,or related materials; (d) α-glucosidase inhibitors (e.g., acarbose); (e)cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, and other statins), (ii) sequestrants (e.g., cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPAR-α agonists (e.g., fenofibric acid derivatives includinggemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) inhibitorsof cholesterol absorption (e.g., β-sitosterol) and acyl CoA:cholesterolacyltransferase inhibitors (e.g., melinamide), and (vi) probucol; (f)PPAR-α/γ agonists; (g) antiobesity compounds (described previously); (h)ileal bile acid transporter inhibitors; (i) insulin receptor activators,(j) dipeptidyl peptidase IV, or DPP-4 inhibitors (sitagliptin,vildagliptin and other DPP-4 inhibitors (k) exenatide, (l) pramLintide,(m) FBPase inhibitors, (n) glucagon receptor antagonists, (o)glucagon-like peptide-1, and (p) the glucagon-like peptide-1 analogues(liraglutide, and others).

The compounds of the present invention are expected to be CB1 receptorblockers and are expected to be useful for treating diseases mediated bythe CB₁ receptor. The compounds of the present are expected to possessan affinity in vitro for the central and/or peripheral cannabinoidreceptors under the experimental conditions described by Devane et al.,Molecular Pharmacology, 1988, 34, 605-613. The compounds according tothe invention are also expected to possess an affinity for thecannabinoid receptors present on preparations of electrically stimulatedisolated organs. These tests can be performed on guinea-pig ileum and onmouse vas deferens according to Roselt et al., Acta PhysiologicaScandinavia 1975, 94, 142-144, and according to Nicolau et al., Arch.Int. Pharmacodyn, 1978, 236, 131-136.

CB1 receptor affinities can be determined using membrane preparations ofChinese hamster ovary (CHO) cells in which the human cannabinoid CB1receptor is stably transfected (Biochem J. 1991, 279, 129-134) inconjunction with [3H]CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [3H]-radioligand,with or without addition of test compound, separation of bound and freeligand is performed by filtration over glass fiber filters.Radioactivity on the filter is measured by liquid scintillationcounting. The IC₅₀ values can be determined from at least threeindependent measurements.

Formulations and Dosages

In the present invention, the compound(s) of the present invention canbe administered in any convenient manner (e.g., enterally orparenterally). Examples of methods of administration include orally andtransdermally. One skilled in this art is aware that the routes ofadministering the compounds of the present invention may varysignificantly. In addition to other oral administrations, sustainedrelease compositions may be favored. Other acceptable routes may includeinjections (e.g., intravenous, intramuscular, subcutaneous, andintraperitoneal); subdermal implants; and, buccal, sublingual, topical,rectal, vaginal, and intranasal administrations. Bioerodible,non-bioerodible, biodegradable, and non-biodegradable systems ofadministration may also be used. Examples of oral formulations includetablets, coated tablets, hard and soft gelatin capsules, solutions,emulsions, and suspensions.

If a solid composition in the form of tablets is prepared, the mainactive ingredient can be mixed with a pharmaceutical vehicle, examplesof which include silica, starch, lactose, magnesium stearate, and talc.The tablets can be coated with sucrose or another appropriate substanceor they can be treated so as to have a sustained or delayed activity andso as to release a predetermined amount of active ingredientcontinuously. Gelatin capsules can be obtained by mixing the activeingredient with a diluent and incorporating the resulting mixture intosoft or hard gelatin capsules. A syrup or elixir can contain the activeingredient in conjunction with a sweetener, which is typicallycalorie-free, an antiseptic (e.g., methylparaben and/or propylparaben),a flavoring, and an appropriate color. Water-dispersible powders orgranules can contain the active ingredient mixed with dispersants orwetting agents or with suspending agents such as polyvinylpyrrolidone,as well as with sweeteners or taste correctors. Rectal administrationcan be effected using suppositories, which are prepared with bindersmelting at the rectal temperature (e.g., cocoa butter and/orpolyethylene glycols). Parenteral administration can be effected usingaqueous suspensions, isotonic saline solutions, or injectable sterilesolutions, which contain pharmacologically compatible dispersants and/orwetting agents (e.g., propylene glycol and/or polyethylene glycol). Theactive ingredient can also be formulated as microcapsules ormicrospheres, optionally with one or more carriers or additives. Theactive ingredient can also be presented in the form of a complex with acyclodextrin, for example α-, β-, or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the compound of the present invention administered dailywill vary on an individual basis and to some extent may be determined bythe severity of the disease being treated (e.g., obesity, diabetes,liver diseases, cardiometabolic disorders, and cancers). The dose of thecompound of the present invention will also vary depending on thecompound administered. Examples of dosages of compounds of the presentinvention include from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07,0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4,5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76,80, 85, 90, 95, to 100 mg/kg of mammal body weight. The compound can beadministered in a single dose or in a number of smaller doses over aperiod of time. The length of time during which the compound isadministered varies on an individual basis, and can continue until thedesired results are achieved (i.e., reduction of body fat, or preventionof a gain in body fat). Therapy could, therefore, last from 1 day toweeks, months, or even years depending upon the subject being treated,the desired results, and how quickly the subject responds to treatmentin accordance with the present invention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 Whitecorn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Capsule Active ingredient 50 Crystalline lactose 60Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fillweight 150

In the above capsule, the active ingredient has a suitable particlesize. The crystalline lactose and the microcrystalline cellulose arehomogeneously mixed with one another, sieved, and thereafter the talcand magnesium stearate are admixed. The final mixture is filled intohard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention isas follows.

Ingredient mg/Solution Active substance 1.0 mg 1N HCl 20.0 μl aceticacid 0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1N NaOH q.s. ad pH 5 H₂O q.s. ad1 mLSynthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis (e.g., seeU.S. Pat. No. 6,476,060 B2, J Med Chem 2004, 47, 627). The compounds ofthe present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Scheme 1 shows how to convert 2′-, 3′-, or4′-(carbo-t-butoxymethoxy)-2-phenylacetophenones, prepared fromcommercially available 2′-, 3′- or 4′-methoxy-2-phenylacetophenones viaO-demethylation using HBr/HOAc or BBr₃/CH₂Cl₂ and alkylation of theresultant phenol with t-butyl bromoacetate in the presence of base, in37% aqueous formaldehyde containing piperidine under reflux to thecorresponding acrylophenones (step a). Treatment of the acrylophenoneswith hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines(step b). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters, prepared from thecorresponding aryl sulfonamides, CS₂ and MeI (see J. Med. Chem., 47, 627(2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) inthe presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Hydrolysis of the ester usingTFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 2 describes how 2-(2′-, 3′- or4′-carbo-t-butoxymethoxyphenyl)acetophenones (prepared similarly toscheme 1) should provide the corresponding acrylophenones (step a).Treatment of the acrylophenones with hydrazine hydrate in ethanol canproduce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can befurther treated with arylsulfonyldithioimidocarbonic acid methyl estersin a solvent like acetonitrile in the presence of triethylamine atreflux to yield pyrazole-1-carboximidothioic acid methyl esters (stepc). Further exposure of these iminothioethers to an aqueous solution ofmethylamine and methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Hydrolysis of the ester usingTFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 3 shows the conversion of 4′-chloro-2-phenylacetophenone in 37%aqueous formalin and MeOH containing piperidine and acetic acid atreflux that should occur affording the acrylophenone (J. Agric. FoodChem. 1979, 27(2), 406)(step a). Treatment of the acrylophenone withhydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (stepb). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to beta-alanine t-butyl ester inethanol and methylene chloride containing triethylamine should yield thepyrazoline-esters (step d). Hydrolysis of the ester using TFA/CH₂Cl₂should produce the carboxylic acid (step e). Treatment of the ester withanhydrous ammonia in methanol at about 0° to room temperature can affordthe carboxamido compound (step f). Alternatively, the iminothioetherscan be coupled with other amino acid esters to give adducts (step g)that can be hydrolyzed to the carboxylic acids (step h). These acids maybe converted to the carboxamides using oxalyl chloride in dichloroethanefollowed by anhydrous ammonia, or Boc₂O in pyridine/THF followed byanhydrous ammonia (step i).

Scheme 4 illustrates how oxidation of 4′-chloro-2-phenylacrylophenone inmethylene chloride with m-chloroperbenzoic acid should provide theepoxide (step a), which upon treatment with hydrazine hydrate in ethanolsolution at about 35-40° C. can give the 3,4-diarylpyrazoline alcohol(step b). The pyrazoline can be protected using di-t-butyl-dicarbonate(t-Boc anhydride) in the presence of a base to give theN-t-BOC-pyrazoline (step c). The carbamate alcohol can then bedeprotonated with sodium hydride in a solvent like DMF followed byalkylation with ethyl 4-bromocrotonate to yield the ester (step d).Removal of the t-BOC group can be achieved via treatment with TFA (stepe). The pyrazoline can then be reacted witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ether (step f). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature can afford thepyrazoline-1-carboxamidines (step g), and hydrolysis of the ester usingLiOH in aqueous THF solution can produce the carboxylic acid (step h).The carboxamides can be prepared by treatment of the ester withanhydrous ammonia in alcohol at −20° C. to ambient temperature (step i).

Scheme 5 shows how heating a solution of the 3,4-diarylpyrazoline andS-methylisothiourea in pyridine can form the pyrazoline-1-carboxamidine(step a). Treatment of this amidine with t4-cyanobenzenesulfonylchloride in acetonitrile in the presence of N,N-dimethyl-4-aminopyridineand triethylamine can give the carboxamidine-coupled sulfonamidederivative (step b). Conversion of the nitrile to thephenylcarboxamidine can be accomplished using HCl (gas) in MeOH at 0° C.to room temperature, followed by ammonium carbonate or anhydrous ammoniain MeOH at about 0° C. to room temperature (step c).

Scheme 6 describes how the reaction of a freshly prepared anhydrousacetonitrile solution of 4-chlorobenzoylisothiocyanate, made from4-chlorobenzoylchloride and ammonium isocyanate (see J Heterocycl. Chem.1991, 28, 1645), and a 3,4-diarylpyrazoline stirred in the cold canafford the pyrazoline—adduct (step a). Treatment of this thiocarboxamidewith amino compounds such as ethyl beta-alanine in the presence of HgCl₂can produce the benzoyl guanidines (step b). Hydrolysis of the esterusing LiOH in aqueous THF solution can produce the carboxylic acid (stepc). Further conversion of the acid to the acid chloride followed bytreatment with anhydrous ammonia should afford the carboxamide (step d).

Scheme 7 depicts how condensation of a solution of4′-nitro-2-phenylacetophenone in 37% aqueous formalin and MeOHcontaining piperidine and acetic acid should afford after heating atreflux, the corresponding acrylophenone (step a). Treatment of theacrylophenone with hydrazine hydrate in ethanol can produce the3,4-diarylpyrazoline (step b). The pyrazoline can then be reacted witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thecorresponding pyrazole-1-carboximidothioic acid methyl ester (step c).The nitro group can be reduced using sodium dithionite in aqueous basicsolution to produce the aniline compound (step d). Acylation of theaniline with ethyl malonyl chloride in the presence of base shouldproduce the amide (step e). Treatment of the amidoester with amines suchas methylamine or anhydrous ammonia in a solvent such as methanol ormethylene chloride at zero degrees to room temperature should afford thepyrazole-1-carboxamidines with the terminal carboxamido group (step f).Alternatively, the aniline compound can be treated with methanesulfonylchloride to give the sulfonamide (step g), which upon exposure to anaqueous solution of methylamine and methylene chloride at roomtemperature should afford the pyrazoline-1-carboxamidines (step h).

Scheme 8 illustrates how treatment of 4′-cyano-2-phenylacrylophenonewith hydrazine hydrate in ethanol will produce the 3,4-diarylpyrazoline(step a). The pyrazoline can then be reacted with tri-n-butyltin azide,conveniently prepared in situ by the reaction of one equivalent ofsodium azide and one equivalent of tri-n-butyltin chloride (see J. Med.Chem. 1991, 56, 2395), in reluxing toluene or xylene to afford thetri-n-butyltin-tetrazole adduct (step b). The tri-n-butyltin-adduct canbe converted to the trityl-tetrazole adduct by treatment with oneequivalent of aqueous sodium hydroxide solution and one equivalent oftrityl chloride at room temperature (step c). Reaction of this adductwith arylsulfonyldithioimidocarbonic acid methyl esters in a solventlike acetonitrile in the presence of triethylamine at reflux shouldyield the pyrazole-1-carboximidothioic acid methyl ester (step d).Treatment of the iminothioether with aqueous methylamine and methylenechloride at room temperature should afford the pyrazole-1-carboxamidines(step e). Removal of the trityl group with aqueous TFA in THF at roomtemperature should yield the unprotected tetrazole (step f).

Scheme 9 shows how to convert 2′-, 3′-, or 4′-polyethoxylated analogs of2-phenylacetophenones, prepared from commercially available 2′-, 3′- or4′-methoxy-2-phenylacetophenones via O-demethylation using HBr/HOAc orBBr₃/CH₂Cl₂ and alkylation of the resultant phenols with alkyl-capped orTBDMS-capped halides prepared as described in Nuclear Medicine andBiology, 32, 799 (2005). Treatment of these polyether ketones in 37%aqueous formaldehyde containing piperidine under reflux should give thecorresponding acrylophenones (step a). Treatment of the acrylophenoneswith hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines(step b). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters, prepared from thecorresponding aryl sulfonamides, CS₂ and MeI (see J. Med. Chem., 47, 627(2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) inthe presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Removal of the TBDMS-capping groupusing anhydrous tetrabutylammonium fluoride in THF should produce thehydroxyl-PEG analog (step e).

One stereoisomer of a compound of the present invention may be a morepotent cannabinoid receptor antagonist than its counterpart(s). Thus,stereoisomers are included in the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such asdescribed in Wilen, S. H. Tables of Resolving Agents and OpticalResolutions 1972, 308 or using enantiomerically pure acids and bases. Achiral compound of the present invention may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis. Examples of stereoisomers include compoundsshown below.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The following examples are representative of the procedures used toprepare the preferred compounds in this application.

Abbreviations:

MeOH-methanol

DCM-dichloromethane

EtOAc-ethyl acetate

HCl-hydrochloric acid

PE-petroleum ether

NMM-N-methylmorpholine

IBCF-iso-butylchloroformate

TEA-triethylamine

The preparation of the diphenyl pyrazolines with optional substituentson the 3-phenyl group were prepared according to the procedurespreviously described [J. Med. Chem., 47, 627 (2004); J. Agric. FoodChem., 27, 406 (1979)]. The pyrazolines were condensed with sulfonylatedcarbamic acid methyl esters obtained from the appropriately substitutedsulfonamide and methyl chloroformate as previously described.Chlorination of the product acylsulfonamides with phosphoruspentachloride in heated cholorbenzene produced the imidoylchlorideswhich were readily converted to the various amino ester adducts aspreviously described [J. Med. Chem., 47, 627 (2004)]. The aminophophosphonate esters can be prepared through standard Kabachnik-Fieldschemistry: see Tetrahedron, 59, 5329 (2003) and references therein; and,Angew. Chem., Int. Ed., 47, 5079 (2008). Conversion of these esters toacids, carboxamides, substituted carboxamides, or di-amino acid variantswere carried via conventional methodology, and procedures representativeof this chemistry are described below.

Example 1

To 10 mmoles of imidoyl chloride suspended in 20 mL of DCM was addeddropwise to a cooled solution of 12 mmols of glycine methyl esterhydrochloride salt and 25 mmoles of TEA in 50 mL DCM, after theaddition, the reaction mixture was allowed to warm to ambienttemperature. After stifling for about one hour, the solvent was removedin vacuo and water (50 mL) was added and the mixture was extracted withEtOAc. The combined extracts were washed with brine, and then dried overanhydrous Na₂SO₄. After solvent removal in vacuo the residue waspurified by silica gel column chromatogram (PE/EtOAc: 2/1) to afford thecarboxamidine (50-80% yields).

Example 2

Lithium hydroxide monohydrate (10 mmoles) and 5 mmoles of carboxamidineester in THF (50 mL) and water (16 mL) was stirred at room temperaturefor 5-7 hrs. The pH of the solution was then adjusted to ˜1-2 by theaddition of 1N HCl solution, and the solvent was removed under reducedpressure. Water (15 mL) was added to the residue which was thenextracted with EtOAc. The combined extracts were washed with brine anddried over anhydrous Na₂SO₄. The carboxylic acid products (70-95%yields) were obtained by evaporation of the solvent in vacuo.

Example 3

The carboxylic acids (1 mmol), obtained from the ester by the proceduredescribed in Example 2, in 40 mL of dry DCM containing NMM (3 mmol) wascooled to about −15° C. with a salt ice bath. A solution of IBCF (1.1mmol) in dry DCM (20 mL) was added dropwise over a 5 min period andafter stifling for 20 mins in an ice-brine bath, dry ammonia/THFsolution was added in one portion, and the reaction mixture was thenallowed to slowly warm to rt where it was stirred for 20 mins. Thesolvent was removed by evaporation, and the residue was diluted with 20mL of water and extracted with EtOAc. The combined extracts were washedwith 15 mL of 1N HCl solution and 30 mL of brine, and then dried overanhydrous Na₂SO₄. After filtration of the solution and removal of thesolvent in vacuo, the residue was purified by silica gel chromatographyto give the carboxamide adduct (60-80% yields).

Table 1 shows compounds of the present invention synthesized by theroute described in Scheme 3. The CB₁ IC₅₀ values for tested compoundsare as follows.

TABLE 1

Ex. CB1 # Q Y″ X″ X IC₅₀ NMR ppm  1 CHCH₃CONH₂ 4-Cl H OMe +++ (CDCl₃)CH₃, 1.56, (3H, dd) OMe, 3.77 (3H, s) CH, 3.95, 4.11, (1H, 2 dd) CH,4.45, 4.50 (1H, 2 t) CH, 4.65 (1H, dd) CH, 4.72, 4.82 (1H, 2 t) NH, 5.48(1H, brd s) NH, 6.43 (1H, brd s) aromatic Hs, 6.79-7.87 (13H)  2CH(CH₂OH)CONH₂ 4-Cl H Cl +++ (CDCl₃) CH₃, 1.29, (3H, m) CH, 3.95, 4.10(1H, 2 dd) CH₂, 4.50 (2H, brd m) CH, 4.70 (1H, brd m) NH, 5.10 (1H, s)NH, 5.80 1H (brd s) aromatic Hs 7.11-7.85, (13H)  3 CH₂CH₂SO₂NH₂ 4-Cl HCl +++ (CDCl₃) CH₂SO₂ 3.54 (2H, brd s) CH, 4.03 (1H, dd) NCH₂, 4.15 (2H,brd s) CH, 4.49 (1H, t) CH, 4.68 (1H, dd) NH, 5.36 (2H, s) aromatic Hs7.09-7.84, (13H) NH, 7.62 (1H, brd m)  4 CH[CH(CH₃)₂]CONH₂ 3-CONH₂ H Cl++ (CD₃OD) CH₃, 1.01, (6H, m) CH, 2.28 (1H, brd m) 4.10 CH (1H, brd m)4.52, CH, (1H, m) aromatic Hs 7.19-8.10, (13H)  5 CH[CH(CH₃)₂]CONH₂ 3-CNH Cl +++ (CDCl₃) CH₃, 1.09, (6H, m) CH, 2.38 (1H, brd m) CH, 3.95 (1H,brd s) CHs, 4.50-4.70 (3H, brd m) NH, 6.60 (1H, brd s) aromatic Hs7.19-8.22, (13H) NH, 8.13 (1H, d)  6 CH₂C(NOH)NH₂ 4-Cl H Cl +++ (CDCl₃)CH, 4.13 (1H, dd) CH₂, 4.25 (2H, collapsed q) CH, 4.60 (1H, t) CH, 4.72(1H, dd) NH, 5.19 (2H, brd s) aromatic Hs 7.10-7.87, (13H)  7CH(CHOHCH₃)CONH₂ 4-Cl H Cl +++ (CDCl₃) CH₃, 1.29, (3H, m) CH, 3.95, 4.10(1H, 2 dd) CH₂, 4.50 (2H, brd m) CH, 4.70 (1H, brd m) NH, 5.10 (1H, s)NH, 5.80 1H (brd s) aromatic Hs 7.11-7.85, (13H)  8 CH₂CH₂C(NOH)NH₂ 4-ClH Cl +++ (CDCl₃) CH₂C(NOH) 2.54 (2H, t) NCH₂, 3.90 (2H, q) CH, 4.05 (1H,dd) CH, 4.48 (1H, t) CH, 4.64 (1H, dd) NH, 4.85 (2H, brd s) aromatic Hs7.10-7.86, (13H)  9 CH[CH(CH₃)₂]CONH₂ 3-C(NH)NH₂ H Cl ++ (CD₃OD) CH₃,1.05, (6H, m) CH, 2.33 (1H, brd m) 4.10 CH (1H, brd m) 4.55, CH, (1H, m)aromatic Hs 7.19-8.45, (13H) 10 C[(CH₂)₃]CONH₂ 3-OCH₃ H Cl +++ (CDCl₃)CH 1.92 (1H, brd s) CH 2.05 (2H, brd s) CH 2.17 (1H, brd s) CH 2.75 (1H,brd s) CH 2.87 (1H, brd s) OCH₃, 3.81 (3H, s) CH, 4.12 (1H, m) CH, 4.50(1H, brd s) CH, 4.61 (1H, brd s) NH, 5.45 (1H, brd s) NH, 6.19 (1H, brds) aromatic Hs 7.03-7.60, (13H) NH, 8.13 (1H, brd s) 11CH(CHOHCH₃)CONHCH(CH₂OH)CONH₂ 4-Cl H Cl +++ (CD₃OD) CH₃, 1.25, (3H, m)CH, 3.87, (3H, brd m) CHOHMe, 4.13 (1H brd m) CH₂, 4.37-4.60 (3H, brd m)CH, 4.80 (1H, brd m) aromatic Hs 7.18-7.92, (13H) 12 CH(CHOHCH₃)CONH₂3-CN H Cl +++ (CDCl₃) CH₃, 1.29, (3H, m) CH, 3.95, 4.12 (1H, 2 dd) CH,4.50 (2H, brd m) CH, 4.73 (2H, brd m) NH, 5.80 (1H, brd s) NH, 7.05 1H(brd m) aromatic Hs 7.11-8.25, (13H) 13 CH(CHOHCH₃)CONH₂ 3-C(NH)NH₂ H Cl+++ (CDCl₃) CH₃, 1.40, (3H, m) OCH, 3.63, 3.64 (3H, 2 s) CH, 4.05 (2H,brd m) CH, 4.68 (2H, brd m) CH, 4.95 (1H, brd m) NH, 6.10 (1H, brd s)NH, 5.80 1H (brd s) aromatic Hs 7.11-8.50, (13H) NH, 8.04 (1H, dd) 14CH₂CH₂SO₂NH₂ 3-OCH₃ H Cl +++ (CDCl₃) CH₂SO₂ 3.51 (2H, t) OCH₃, 3.80 (3H,s) CH, 4.07 (1H, dd) NCH₂, 4.15 (2H, brd s) CH, 4.54 (1H, t) CH, 4.67(1H, dd) NH, 5.19 (2H, s) aromatic Hs 7.10-7.55, (13H) NH, 7.57 (1H, t)15 CH₂CH₂SO₂NH₂ 3-CN H Cl +++ (CDCl₃) CH₂SO₂ 3.53 (2H, t) CH, 4.10 (1H,dd) NCH₂, 4.18 (1H, dd) CH, 4.53 (1H, t) CH, 4.71 (1H, dd) NH, 5.08 (2H,s) aromatic Hs 7.11-8.20, (13H) NH, 7.60 (1H, t) 16 CHCH₃CONH₂ 3-CN H Cl+++ (CDCl₃) CH₃ 1.59 (3H, d) CH 4.03, 4.13 (1H, 2 m) CH 4.54 (1H, m) CH4.70 (1H, m) CH 4.80 (1H, m) NH, 5.69 (1H, brd s) NH, 6.29 (1H, brd s)aromatic Hs 7.09-8.23, (13H) NH, 8.13 (1H, brd s) 17 C[(CH₂)₃]CONH₂ 3-CNH Cl +++ (CDCl₃) CH 2.03 (1H, brd s) CH 2.14 (3H, brd m) CH 2.78 (1H,brd s) CH 2.90 (1H, brd s) CH, 4.10 (1H, brd s) CH, 4.51 (1H, brd s) CH,4.64 (1H, brd s) NH, 5.50 (1H, brd s) NH, 6.20 (1H, brd s) aromatic Hs7.05-8.22 (13H) NH, 8.13 (1H, brd s) 18 CHCH₃CONH₂ 3-OMe H Cl +++(CDCl₃) CH₃ 1.57 (3H, d) OCH₃ 3.80 (3H, s) CH 4.13 (1H, brd d) CH 4.59(1H, t) CH 4.67 (1H, m) CH 4.73 (1H, m) NH, 5.79 (1H, brd s) NH, 6.45(1H, brd s) aromatic Hs 7.07-7.55, (13H) NH, 7.6 (1H, brd s) 19CH[CH(CH₂)₃]CONH₂ 4-Cl H Cl +++ (CDCl₃) CH 0.54 (1H, m) CH 0.63 (1H, m)CH 0.77 (2H, m) CH 1.30 (1H, m) CH 3.99 (1H, dd) CH 4.11 (1H, t) CH 4.55(1H, t) CH 4.63 (1H, dd) NH 5.60, 5.70 (1H, 2 brd s) NH 6.30 (1H, brd s)aromatic Hs 7.07-7.88, (13H) NH, 7.70 (1H, brd s) 20 CH₂CH₂SO₂NH₂ 4-Cl HOMe +++ (CDCl₃) CH₂SO₂ 3.52 (2H, t) OCH₃, 3.76 (3H, s) CH, 4.01 (1H, dd)NCH₂, 4.16 (2H, m) CH, 4.49 (1H, t) CH, 4.64 (1H, dd) NH, 5.19 (2H, s)aromatic Hs 6.77-7.88, (13H) NH, 7.55 (1H, t) 21 CH[CH(CH₂)₂]CONH₂ 3-OMeH Cl ++ (CDCl₃) CH, 0.53 (1H, m) CH, 0.62 (1H, m) CH, 0.77 (2H, brd m)CH, 1.28 (1H, m) OCH₃ 3.80 (3H, s) CH 4.02 (1H, dd) CH 4.12 (1H, m CH4.57 (1H, t) CH 4.62 (1H, dd) NH, 5.50, 5.56 (1H, 2 brd s) NH, 6.30 (1H,brd s) aromatic Hs 7.09-7.54, (13H) NH, 7.70 (1H, brd s) 22CH[CH(CH₂)₃]CONH₂ 3-CN H Cl +++ (CDCl₃) CH, 0.56 (1H, m) CH, 0.60 (1H,m) CH, 0.76 (2H, brd m) CH, 1.29 (1H, m) CH 4.02 (1H, dd) CH 4.14 (1H,m) CH 4.57 (1H, t) CH 4.62 (1H, m) NH, 5.70 (1H, brd s) NH, 6.23 (1H,brd s) aromatic Hs 7.09-8.24, (13H) NH, 7.67 (1H, brd s) 23CH₂CONHCH₂CH₂SO₂NH₂ 4-Cl H Cl +++ (CDCl₃) CH₂SO₂ 3.33 (2H, brd s) NCH,3.74 (2H, brd s) CH, 3.98 (1H, m) NCHCO, 4.34 (2H, brd s) CH, 4.49 (1H,t) CH, 4.65 (1H, m) NH, 5.66 (2H, s) aromatic Hs 7.10-7.86, (13H) NH,7.55 (1H, t) 24 CH₂CH═CHCO₂CH₃ 4-Cl H Cl +++ (CDCl₃) OCH₃, 3.77 (3H, 3)CH, 4.17 (1H, brd s) CH, 4.39 (2H, m) CH 4.63 (2H, m) CH, 5.95 (1H, d)CH, 6.97 (1H, dt) aromatic Hs 7.10-7.84, (13H) 25CH(CHOHCH₃)CONHCH₂CH₂SO₂NH₂ 4-Cl H Cl +++ (CD₃OD) CH₃, 1.22, (3H, m)SO₂CH, 3.26, (2H, brd m) NCH₂, 3.60-3.85 (3H, brd m's) CHOH, 4.17 (1H,brd m) CH, 4.34 (1H, brd s) CH, 4.50 (1H, brd m) CH, 4.90 (1H, brd m)aromatic Hs 7.20-7.92, (13H) 26 CH(CH₂OH)—CONHCH₂—CH₂SO₂NH₂ 4-Cl H Cl+++ (CD₃OD) SO₂CH, 3.25, (2H, brd m) CH, 3.65 (2H, brd m) CH, 3.85 (2H,brd m) CH, 4.00 (1H, brd m) CH, 4.45 (1H, brd m) CH, 4.90 (1H, brd m)aromatic Hs 7.20-7.92, (13H) 27

4-Cl H Cl + (CDCl₃) CH₂CO 3.55 (2H, s) CH 4.75 (1H, brd s) CH 4.92 (1H,m) CH 5.15 (1H, t) NH, 5.84 (1H, brd s) NH, 6.40 (1H, brd s) CH(thiazole) 6.56 (1H, s) aromatic Hs 7.18-7.92, (13H) NH, 9.85 (1H, brds) 28 CHCH₃PO(OEt)₂ 4-Cl H Cl + (CD₃SOCD₃) CH₃, 1.19, (6H, m) CH₃, 1.33,(3H, m) CH, 4.30 (1H, brd s) CH, 4.48 (1H, t) CH, 5.10 (1H, brd s)aromatic Hs 7.21-7.87, (13H) NH, 7.98 (1H, brd s) 29 CH(C₆H₅)CONH₂ 4-ClH Cl (CD₃SOCD₃) CH, 3.57, 4.00, (1H, 2 brd s) CH, 4.38, (1H, brd m) CH,4.78, 4.93 (1H, 2 brd s) CH, 5.78, 6.02 (1H, 2 brd s) NH, 6.42 (1H, brds) aromatic Hs 7.21-7.87, (18H) NH, 8.40, 8.65 (1H, 2 brd s) +1000-10,000 nM ++ 100-1,000 nM +++ <100 nM

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

What is claimed is:
 1. A compound selected from the compounds 2, 4-6,8-17, 19, or 21-29:

Ex. # Q Y″ X″ X  2 CH(CH₂OH)CONH₂ 4-Cl H Cl  4 CH[CH(CH₃)₂]CONH₂ 3-CONH₂H Cl  5 CH[CH(CH₃)₂]CONH₂ 3-CN H Cl  6 CH₂C(NOH)NH₂ 4-Cl H Cl  8CH₂CH₂C(NOH)NH₂ 4-Cl H Cl  9 CH[CH(CH₃)₂]CONH₂ 3-C(NH)NH₂ H Cl 10C[(CH₂)₃]CONH₂ 3-OCH₃ H Cl 11 CH(CHOHCH₃)CONH— 4-Cl H Cl CH(CH₂OH)CONH₂12 CH(CHOHCH₃)CONH₂ 3-CN H Cl 13 CH(CHOHCH₃)CONH₂ 3-C(NH)NH₂ H Cl 14CH₂CH₂SO₂NH₂ 3-OCH₃ H Cl 15 CH₂CH₂SO₂NH₂ 3-CN H Cl 16 CHCH₃CONH₂ 3-CN HCl 17 C[(CH₂)₃]CONH₂ 3-CN H Cl 19 CH[CH(CH₂)₂]CONH₂ 4-Cl H Cl 21CH[CH(CH₂)₂]CONH₂ 3-OMe H Cl 22 CH[CH(CH₂)₃]CONH₂ 3-CN H Cl 23CH₂CONHCH₂CH₂SO₂NH₂ 4-Cl H Cl 24 CH₂CH═CHCO₂CH₃ 4-Cl H Cl 25CH(CHOHCH₃)CONHCH₂— 4-Cl H Cl CH₂SO₂NH₂ 26 CH(CH₂OH)—CONHCH₂— 4-Cl H ClCH₂SO₂NH₂ 27

4-Cl H Cl 28 CHCH₃PO(OEt)₂ 4-Cl H Cl 29 CH(C₆H₅)CONH₂ 4-Cl H Cl

or a stereoisomer or a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1, wherein the compound is Compound 2 or astereoisomer or a pharmaceutically acceptable salt thereof.
 3. Acompound of claim 1, wherein the compound is Compound 4 or astereoisomer or a pharmaceutically acceptable salt thereof.
 4. Acompound of claim 1, wherein the compound is Compound 5 or astereoisomer or a pharmaceutically acceptable salt thereof.
 5. Acompound of claim 1, wherein the compound is Compound 6 or astereoisomer or a pharmaceutically acceptable salt thereof.
 6. Acompound of claim 1, wherein the compound is Compound 8 or astereoisomer or a pharmaceutically acceptable salt thereof.
 7. Acompound of claim 1, wherein the compound is Compound 9 or astereoisomer or a pharmaceutically acceptable salt thereof.
 8. Acompound of claim 1, wherein the compound is Compound 10 or astereoisomer or a pharmaceutically acceptable salt thereof.
 9. Acompound of claim 1, wherein the compound is Compound 11 or astereoisomer or a pharmaceutically acceptable salt thereof.
 10. Acompound of claim 1, wherein the compound is Compound 12 or astereoisomer or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 12. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of claim 2 and a pharmaceuticallyacceptable carrier.
 13. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound of claim 3 and apharmaceutically acceptable carrier.
 14. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound of claim 4and a pharmaceutically acceptable carrier.
 15. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of claim 5 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound of claim 6 and a pharmaceutically acceptablecarrier.
 17. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of claim 7 and a pharmaceuticallyacceptable carrier.
 18. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound of claim 8 and apharmaceutically acceptable carrier.
 19. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound of claim 9and a pharmaceutically acceptable carrier.
 20. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of claim 10 and a pharmaceutically acceptable carrier.